Cognitive impairment is an important public health concern in the United States yet therapeutic options for its treatment remain limited. Clinical and experimental studies indicate that a cholinergic deficit plays an important role in the pathogenesis of cognitive impairment. Thus cholinergic systems offer a good target for the rational development of novel therapeutic approaches. Unfortunately efforts in this direction are currently hampered by a limited understanding of cholinergic mechanisms in the cerebral cortex. Therefore the long term goal of this proposal is to develop a cellular and molecular understanding of the mechanisms by which acetylcholine regulates neuronal excitability in association cortex. Previous studies have used electrophysiological methods to investigate cholinergic regulation of neuronal function. These have focused mostly on hippocampus where they have identified a variety of potassium currents that are inhibited by muscarinic receptors. Studies during the last few years however suggest that the information obtained in hippocampus is not directly transposable to cortex and especially association regions of cortex. Since these areas are important in mediating higher cognitive function, there is a pressing need to investigate the mechanisms by which cholinergic receptors regulate neuronal excitability in these regions. To address this problem the present application proposes to investigate cholinergic mechanisms in rat prefrontal cortex, an associative area. In particular it seeks to identify and characterize a novel muscarinic regulated calcium-activated inward current present in this region. Following completion of this aim it proposes to test the hypothesis that different receptors subtypes and transduction mechanisms participate in the signalling of cholinergic responses in this region. Finally, it concludes by proposing to assess the role of these receptors in mediating cholinergic neurotransmission. These experiments should further our understanding of the cellular and molecular mechanisms by which acetylcholine regulates cortical function. As such they should contribute to efforts aimed at developing novel and effective therapeutic strategies for the treatment of diseases associated with cognitive impairment.